In America and Western Europe, renal/ureteral calculi (stones) occur at least once in the lifetimes of 12-15% of men and 4-6% of women. The annual incidence of renal/ureteral stones has been reported to be around 2-3% of this population. The most common presenting symptom is severe flank pain which is often referred to as “acute ureteral colic” or “renal colic.” The stones need to be removed via urologic procedures in a third of patients with renal colic, amounting to approximately 500-750 stone-removal procedures per million people annually. Approximately half of the patients with previous urinary calculi have a recurrence within 10 years. Medical emergencies related to stones include unrelieved pain, ureteral obstruction, anuria, infection and acute renal failure, all of which are common reasons for acute hospitalization.
Initial management of kidney and ureteral stones is based on three key concepts: (1) fast and rational diagnostic process; (2) effective pain control; and (3) understanding of the impact of stone location and size on the natural course of the disease. Size of the stone is usually the primary determinant of initial treatment. Stones <5 mm usually pass spontaneously while stones greater than 5 mm are best treated with lithotripsy. More complex stones may require ureteroscopy.
Until little more than 25 years ago, having a ureteral stone >5 mm meant undergoing open surgery. The widespread introduction of devices for extracorporeal shock wave lithotripsy (“ESWL”) greatly reduced the need for such invasive procedures. Studies over the past 25 years have shown that on discharge from ESWL, a third of the patients were stone free, while the remainder had stone dust or passable fragments. At 3-month follow-up the stone-free rate was 65%, and at two years 55% were stone free. Overall, recurrence was observed in 14% and regrowth of fragments was seen in 22% of patients. Residual fragments considered by some to be “clinically insignificant” actually may present an important risk factor for recurrence of stones. These patients certainly need to be monitored and ultimately may need to be pre-emptively treated. Over 20% of patients with persistent residual fragments develop new stones at the site of the fragments.
ESWL has become the standard of treatment for large ureteral calculi and provides an overall stone-free rate of 86-90% for stones <10 mm. One drawback of ESWL, however, is that it often requires repeated treatments. Ultimately, up to 98% of stones can be successfully fragmented by ESWL, but the ability of the kidneys and urethers to clear the resulting fragments is critically important in terms of successful treatment outcomes in that residual lithiases tend to result in re-growth and further progression of stone disease.
Limitations of ESWL include unknown ovarian effects in women of child-bearing age who have middle or distal ureter stones and bleeding disorders. Recent use of NSAIDs is another contraindication to ESWL because of increased risk of perinephric bleeding. Patients should discontinue use of NSAIDS at least 3 days prior to ESWL. ESWL also has been reported to cause renal (subcapsular and perirenal) hematomas which can be responsible for persistent lumbar pain.
Another approach to stones that are not expected to pass spontaneously is ureteroscopy (“URS”). Stones larger than 10 mm are generally better treated with ureteroscopy. However, most urologists prefer ESWL to URS as a first-line treatment because it is less invasive and, unlike URS, it does not require general anesthesia.
A comparison of URS to ESWL indicates shorter hospital stays for the ESWL group. Retreatment rates were lower (but did not reach significance) in the URS group. On the other hand, URS achieves a higher stone-free rate but at the cost of higher complication rates and longer hospital stays. URS is preferred in females of child-bearing age (due to concern about ovarian damage due to ESWL), patients with impacted stones, obstructive uropathy, stones >2 cm and radiotransparent stones. A major disadvantage of ESWL lies in the number of repetitions required and the long wait—often months—until the last fragments pass. However, the need for anesthesia in URS has to be factored in when comparing the two procedures.
Up to 75% of kidney stones will spontaneously pass without the need of ESWL or URS. Two thirds of ureteral stones that pass spontaneously will pass within four weeks after the onset of the symptoms; however, a ureteral stone that has not passed in 4-8 weeks is unlikely to pass spontaneously, and stones that have not passed within 4 weeks have a major complication rate of about 20%. Repeated imaging is warranted to confirm passage of the stone because inappropriate (or unsuccessful) watchful waiting can result in severe and even life-threatening complications such as intractable ureteral strictures (causing chronic pain), anuria, renal failure and sepsis. Even when successful, spontaneous passage of a stone can be painful and temporarily debilitating. Medical treatment and watchful waiting are associated with pain and significant loss of work days.
ESWL and URS are not free of risks and are relatively expensive. An appropriate conservative approach to stone expulsion is generally more cost-effective than any invasive procedure, but only if it results in timely expulsion of the stone. Failure of conservative treatment is far more costly than immediate URS or ESWL because of missed worked days and the need for complex urological care. Overall, watchful waiting without any additional medical treatment results in 25-54% expulsion rates with a mean expulsion time of >10 days and considerable analgesic use even when the stones are <4 mm.
The high incidence of complications of kidney stones has prompted a search for a useful medical (pharmacologic) therapy. As discussed in more detail below, these therapies have included a myriad of intravenous hydration and diuretics, steroids, opioids, progesterone, calcium channel blockers, and alpha-1 blockers, along with the use of various combinations of the foregoing.
The longest-used approach to promote the passage of ureteral stones was vigorous intravenous hydration with the use of diuretics aimed at increasing the pressure in the proximal ureter in order to “push” the stone out. However, a recent review found no credible evidence supporting the use of high volume intravenous fluids or diuretics for the treatment of acute ureteral colic, and such treatment does not address the pain associated with colic.
Methylprednisolone has shown some marginal benefit in facilitating passage of ureteral stones (usually in conjunction with other medications), but has to be used with caution in patients with cardiac disease, hypertension or renal insufficiency. The combination of steroids and nifedipine seems to help in the expulsion of small distal ureteral stones of <1.5 mm.
While opioids are supposed to be the “gold standard” for the treatment of severe pain, it has been found that they are not very effective for ureteral colic and may even hinder the passage of stones.
Hydroxyprogesterone may hasten stone passage and may account for the reduced incidence of symptomatic stones in women.
While some investigators feel that calcium channel blockers increase the rate of spontaneous stone passage in patients who are good candidates for conservative management, others feel that calcium channel blockers have no value in the management of acute ureteral colic.
Many potentially expulsive drugs that have been shown to be effective in animal studies have found limited use in humans due to side effects and toxicities. These include certain antihistamines, parasympatholytic agents and prostaglandins E1 and E2 analogues. Ureteral antispasmodics such as phentolamine and theophylline have shown some effect but their use has been limited by toxicity. The action of nitric oxide (after administration of nitroprusside or glycerol trinitrate [“GTN”]) is to inhibit smooth muscle in the upper urinary tract suggesting potential use of nitric oxide promoters for stone expulsion. In human studies, GTN was mildly effective compared to scopolamine with increased side effects in the GTN group. A trial of GTN patches, however, showed no advantages over placebo for stone passage or for relief of ureteral colic.
Alpha-1 receptor antagonists inhibit basal ureteral tone and decrease peristaltic frequency and amplitude. Muscle cells of the lower urinary tract express two types of alpha-1 receptors (alpha and delta). An inhibitor of these receptors, tamsulosin (Flomax) has been used for years for the treatment of lower urinary tract symptoms in men with prostatism. Tamsulosin significantly reduces ureteral pressure but has no effect on contraction frequency. Tamsulosin has found increasing use as a promoter of stone expulsion in similar doses to those used for lower urinary tract symptoms. At the doses used, the most common reported side effects of tamsulosin are abnormal ejaculation, dizziness and rhinitis.
All of the foregoing treatments are of limited effectiveness, especially with larger calculi. Many of these treatments are associated with significant side effects limiting their usefulness. Accordingly, there remains a great need for improved compositions and methods for treating and preventing urolithiasis and conditions associated therewith.